Dolastatin 10 was first isolated and elucidated by Dr. George R. Pettit and his associates at the Cancer Research Institute at Arizona State University and was found to possess potent cell growth inhibitory powers. (In 1987 the isolation of dolastatin 10 was reported as the most potent (i.e., lowest in vivo dose) antineoplastic substance known to date by G. R. Pettit and his associates (J.Am. Chem. Soc., 1987, 109, 7581-82). However, the vast number of Dolabella needed to provide sufficient Dolastatin 10 to meet the projected public need effectively prevented this remarkable substance from ever being considered for commercial production. Further, the inability to tightly replicate the natural substance from lot to lot because of the entrainment of even slight amounts of unidentifiable impurities in the extracted product created problems which prevented the natural substance from meeting the strict uniformity required as a condition precedent to the approval of the introduction of a new drug product to the market place by the Food, Drug and Cosmetic Administration and corresponding regulatory agencies in other countries.
Because of the very few milligrams of amorphous dolastatin 10 available for structure determination combined with the chiral complexity (nine assymetric centers), the absolute configuration of dolastatin 10 could not be ascertained at that time. Indeed the most attractive solution to both the stereochemical and the preclinical supply problems associated with dolastatin 10 resides in the development of an effective synthesis of the natural isomer from among five hundred twelve possibilities corresponding to the one-dimensional structure.
Thus, the need to develop an economically viable and truly replicable synthetic procedure for producing substantially pure Dolastatin 10 in large quantities is the principal object of the present invention.